The present invention relates to a novel thiol derivative which has an excellent matrix metalloprotease inhibiting activity, and is useful as a therapeutic agent or a prophylactic agent against osteoarthritis and rheumatoid arthritis, and also as an agent for inhibiting the metastasis, the infiltration and the proliferation of various cancers.
A matrix metalloprotease (MMP) is an endopeptidase playing a physiologically important role in tissue reconstruction, and its protease activity is under strict control. However, such control is disturbed in pathological conditions to induce an excessive degradation of the extracellular matrix, thus being involved pathogenically in articular diseases such as osteoarthritis and rheumatoid arthritis, bone diseases such as osteoporosis, periodontosis, tumor infiltration or metastasis, corneal ulceration and the like.
At least 15 types of MMPs are now known, and are classified based on their primary structure and substrate specificity into 5 groups consisting of the collagenase group (MMP-1, 8, 13), the gelatinase group (MMP-2, 9), the stromelysin group (MMP-3, 10), the membrane-type MMP group (MT1, 2, 3, 4-MMP) and the miscellaneous group(MMP-7, 11, 12, 18). Among these groups, MMP-13 in the collagenase group is reported to be expressed exclusively in cartilage and bone tissues and produced at a higher level in articular diseases.
In addition, MMP-13 is assumed to be deeply involved in bone or articular diseases due to its higher collagen degrading activity when compared with other collagenases.
A large number of MMP inhibitors have been reported (Current Pharmaceutical Design, 2, 624-661 (1996)), Expert Opinion on Therapeutic Patents, 6, 1305-1315 (1996), and a large number of thiol derivatives were also reported recently (WO97-3783, WO97-38007, WO97-48685, EP818443, WO98-3164, WO98-3166, WO98-6696, WO98-8814, WO98-12211, WO98-23588, Bioorganic and Medicinal Chemistry Letters, 8, 1157-1162 (1998), Bioorganic and Medicinal Chemistry Letters, 8, 1163-1168 (1998)).
Those also reported in a large number are the compounds exhibiting inhibitory effects on MMP-13, which are classified broadly into hydroxamic acid derivatives (British Journal of Pharmacology, 121, 540-546 (1997), WO97-31892, WO98-15525, WO98-16506, WO98-16520), carboxylic acid derivatives (Journal of Clinical Investigation, 99, 1534-1545 (1997), WO98-6711, WO98-9934, WO98-17643) and thiol derivatives (WO98-3164, WO98-3166).
A novel compound which is more satisfactory when compared with conventional MMP inhibitors in terms of efficacy, duration and safety is desired.
In the course of research under the circumstances described above, we finally discovered that, due to the chemical structure characterized substantially by the substitution of the nitrogen atom on a ring represented by Formula: 
wherein each Y may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR5 (wherein R5 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group, n is an integer of 1 to 3 and q2 is an integer of 0 to 2n+3 with a group represented by Formula: 
wherein ring A and ring B may be same or different and each is an optionally substituted homocyclic or heterocyclic ring, wherein the substituents on ring A (or ring B) are bound to the position capable of being substituted on ring B (or ring A) and taken together with ring A, ring B and X2 to form a condensed ring, X1 is a bond, an optionally substituted divalent C1-3 aliphatic hydrocarbon group or xe2x80x94NR3xe2x80x94 (wherein R3 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), X2 is a bond, an optionally substituted divalent C1-3 aliphatic hydrocarbon group, xe2x80x94NR4xe2x80x94 (wherein R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), xe2x80x94Oxe2x80x94 or xe2x80x94S(O)pxe2x80x94 (wherein p is 0, 1 or 2); and also by the substitution on the carbon atom capable of being substituted on a ring represented by Formula: 
wherein each symbol has a meaning described above with a group represented by Formula: 
wherein each R1 may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR2 (wherein R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), each m may be same or different and is 0 or 1, q1 is an integer of 1 to 2n+4, a compound represented by Formula: 
wherein ring A and ring B may be same or different and each is an optionally substituted homocyclic or heterocyclic ring, wherein the substituents on ring A (or ring B) is bound to the position capable of being substituted on ring B (or ring A) and taken together with ring A, ring B and X2 to form a condensed ring, each R1 may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR2 (wherein R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), X1 is a bond, an optionally substituted divalent C1-3 aliphatic hydrocarbon group or xe2x80x94NR3xe2x80x94 (wherein R3 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), X2 is a bond, an optionally substituted divalent C1-3 aliphatic hydrocarbon group, xe2x80x94NR4xe2x80x94 (wherein R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), xe2x80x94Oxe2x80x94 or xe2x80x94S(O)pxe2x80x94 (wherein p is 0, 1 or 2), each Y may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR5 (wherein R5 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group, each m may be same or different and is 0 or 1, n is an integer of 1 to 3, q1 is an integer of 1 to 2n+4, q2 is an integer of 0 to 2n+3, and the sum of q1 and q2 is 2n+4 or a salt thereof unexpectedly exhibits an excellent MMP inhibiting effect (especially an MMP13 inhibiting effect) resulting from its specific chemical structure in combination with excellent duration and safety, and such pharmacological effect is useful in a prophylactic and therapeutic agent against osteoarthritis, rheumatoidarthritis, osteoporosis, cancer, periodontosis or corneal ulcer, whereby establishing the invention.
Thus, the present invention is:
(1) a compound represented by Formula (I) shown above or a salt thereof (provided that when ring B is a nitrogen-containing heterocyclic ring then X2 binds to a position capable of being substituted except for a nitrogen atom on ring B);
(2) a compound of the above (1) wherein each of ring A and ring B is an optionally substituted benzene ring;
(3) a compound of the above (1) wherein each R1 may be same or different and is a hydrogen atom, an optionally substituted lower alkyl group, xe2x80x94(Cxe2x95x90O)xe2x80x94R6 (wherein R6 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group) or SR2 (wherein R2 has a meaning defined in claim 1);
(4) a compound of the above (1) wherein each R1 may be same or different and is represented by Formula: 
wherein each symbol has a meaning defined in the above (1), or by formula: 
wherein each symbol has a meaning defined in the above (1);
(5) a compound of the above (1) wherein X1 is an optionally substituted methylene group;
(6) a compound of the above (1) wherein X2 is xe2x80x94Oxe2x80x94;
(7) a compound of the above (1) wherein the group represented by Formula: 
in Formula I is a group represented by Formula: 
wherein each of R7 to R11 may be same or different and each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted hydroxy group, an optionally substituted amino group or SR12 (wherein R12 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group) and each of the other symbols has a meaning defined in the above (1);
(8) a compound of the above (1) wherein the group represented by Formula: 
in Formula I is a group represented by Formula: 
wherein each of R13 to R25 may be same or different and each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted hydroxy group, an optionally substituted amino group or SR12 (wherein R12 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group) and each of the other symbols has a meaning defined in the above (1);
(9) a compound of the above (1) wherein m is 0;
(10) a compound of the above (1) which is represented by Formula: 
wherein each symbol has a meaning defined in the above (1);
(11) a method for producing a compound represented by Formula: 
wherein each symbol has a meaning defined in the above (1) or a salt thereof, comprising reacting a compound represented by Formula: 
wherein L is a leaving group and each of the other symbols has a meaning defined in the above (1) or a salt thereof with a compound represented by Formula:
R1SH 
wherein R1 has a meaning defined in the above (1) or a salt thereof;
(12) a method for producing a compound represented by Formula: 
wherein each symbol has a meaning defined in the above (1) or a salt thereof, comprising reacting a compound represented by Formula: 
wherein each symbol has a meaning defined in the above (1) or a salt thereof, or a compound represented by Formula: 
wherein each symbol has a meaning defined in the above (1) or a salt thereof, with a compound represented by Formula:
R1SH 
wherein R1 has a meaning defined in the above (1) or a salt thereof;
(13) a pharmaceutical composition comprising a compound represented by Formula (I) or a salt thereof;
(14) a matrix metalloprotease inhibitor comprising a compound of the above (13) or a salt thereof; and,
(15) a prophylactic and therapeutic agent against osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, periodontosis or corneal ulcer comprising a compound of the above (13) or a salt thereof.
When Compound (I) or a salt thereof contains an asymmetric carbon in its structure, its optically active forms and racemates are also encompassed in the invention, and Compound (I) or a salt thereof may be a hydrate or an anhydride.
The present invention is further detailed below.
Ring A and Ring B
Ring A and ring B may be same or different, and each is a homocyclic or heterocyclic ring having a same or different substituent. Furthermore, the substituents on ring A (or ring B) may be bound to the position capable of being substituted on ring B (or ring A) and taken together with ring A, ring B and X2 to form a condensed ring.
A xe2x80x9chomocyclic or heterocyclic ringxe2x80x9d includes, for example, (i) an aromatic heterocyclic ring or a non-aromatic heterocyclic ring containing, in addition to carbon atoms, 1 or 2 kinds of heteroatoms selected from nitrogen, sulfur and oxygen atoms, preferably the number of heteroatoms is 1 to 3 and (ii) a cyclic hydrocarbon consisting of carbon atoms (homocyclic ring).
An xe2x80x9caromatic heterocyclic ringxe2x80x9d may for example be a 5- or 6-membered aromatic heterocylic ring containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms (for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, etc.).
A preferred aromatic heterocyclic ring may for example be pyridine, pyrazine and thiophene rings as well as pyrrole and thiazole rings, etc.
Those preferred especially are (i) a nitrogen-containing heterocyclic ring containing, in addition to carbon atoms, 1 to 2 nitrogen atoms (for example, pyridine and pyrazine rings), or (ii) a 5-membered aromatic heterocyclic ring containing, in addition to carbon atoms, 1 sulfur atom (for example, thiophene ring).
A xe2x80x9cnon-aromatic heterocyclic ringxe2x80x9d described above includes a 5- to 9-membered non-aromatic heterocylic ring, preferably a 5- to 6-membered non-aromatic heterocylic ring, containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
Those xe2x80x9cnon-aromatic heterocyclic ringxe2x80x9d may typically be tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyrane, dihydropyrrole, dihydroimidazole, dihydropyrazol, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyrane, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole rings, etc.
A xe2x80x9ccyclic hydrocarbon (homocyclic ring)xe2x80x9d described above includes a 3- to 10-membered (preferably 5- to 9-membered) cyclic hydrocarbon, more preferably 5- to 6-membered cyclic hydrocarbon. Those which may be exemplified are benzene, a C3-10 cycloalkene (for example, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), a C3-10 cycloalkane (for example cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc. A cycloalkene is preferably a C5-6 cycloalkene (for example, cyclopentene, cyclohexene, etc.), while a cycloalkane is preferably a C5-6 cycloalkane (for example, cyclohexane, cyclopentane, etc.), etc. Each of ring A and ring B is preferably a 6-membered homocyclic ring such as benzene and cyclohexene rings, etc., particularly a benzene ring.
A substituent which may be possessed by a xe2x80x9chomocyclic or heterocyclic ringxe2x80x9d represented by ring A and ring B may for example be:
(i) a halogen atom (for example, fluorine, chlorine, bromine, iodine atoms, etc.);
(ii) an optionally substituted alkyl group;
(iii) an optionally halogenated alkoxy group (for example, a C1-6 alkoxy group which is substituted optionally with a halogen atom such as fluorine and chlorine atoms, such as methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy groups);
(iv) an optionally halogenated alkylthio group (for example, a C1-6 alkylthio group (especially a C1-4 alkylthio group) which is substituted optionally with a halogen atom such as fluorine and chlorine atoms, etc., such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio groups, etc.);
(v) an aryl group (for example, a C6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl groups, etc.);
(vi) an acyloxy group (for example a C1-3 acyloxy group, etc. such as formyloxy, acetoxy, propionyloxy groups, etc.);
(vii) a hydroxy group;
(viii) a nitro group;
(ix) a cyano group;
(x) an amino group;
(xi) a mono- or dialkylamino group (for example, a mono- or di-C1-6 alkylamino group (especially, mono- or di-C1-4 alkylamino group) such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino groups, etc.);
(xii) a cyclic amino group (for example, a 5- to 9-membered cyclic amino group optionally containing, in addition to carbon atoms, 1 to 3 heteroatoms such as nitrogen, sulfur and oxygen atoms (for example, pyrrolidino, piperidino, morpholino groups, etc.), etc.;
(xiii) an acylamino group (for example, a C1-6 alkyl-carbonylamino group such as formylamino group, or acetylamino, propionylamino, butyrylamino groups, etc.);
(xiv) a lower alkyl-substituted carbamoylamino group (such as ethylcarbamoylamino group, etc.);
(xv) an alkylsulfonylamino group (for example, a C1-6 alkylsulfonylamino group, etc. such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino groups, etc.);
(xvi) an alkoxycarbonyl group (for example, a C1-6 alkoxycarbonyl group, etc. such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl groups, etc.);
(xvii) a carboxyl group;
(xviii) an alkylcarbonyl group (for example a C1-6 alkylcarbonylgroup, etc. such as methylcarbonyl; ethylcarbonyl, butylcarbonyl groups, etc.);
(xix) a carbamoyl group;
(xx) amono- or dialkylcarbamoyl group (for example, a mono- or di-C1-6 alkylcarbamoyl group, etc. such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl groups, etc.);
(xxi) an alkylsulfonyl group (for example, a C1-6 alkylsulfonyl group, etc. such as methylsulfonyl, ethylsulfonyl, propylsulfonyl groups, etc.);
(xxii) an oxo group;
(xxiii) a thioxo group, etc.
An xe2x80x9coptionally substituted alkyl groupxe2x80x9d means, for example:
(a) a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, etc.;
(b) a halogenated C1-6 alkyl group (forexample, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl and perfluorobutyl groups, etc.);
(c) an amino group-substituted C1-6 alkyl group (for example, aminomethyl and 2-aminoethyl groups, etc.);
(d) amono- or di-C1-6 alkylamino-substituted C1-6 alkyl group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);
(e) a carboxyl group-substituted C1-6 alkyl group (for example, carboxymethyl and carboxyethyl groups, etc.);
(f) a C1-6 alkoxycarbonyl-substituted C1-6 alkyl group (for example, methoxycarbonylethyl and ethoxycarbonylethyl groups, etc.);
(g) a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.);
(h) a C6-14 aryl group-substituted C1-6 alkyl group (for example, benzyl, etc.);
(i) a C1-6 alkoxy group-substituted C1-6 alkyl group (for example, methoxymethyl, methoxyethyl, etc.); or,
(j) a C7-15 aralkyloxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl, etc.), etc.
A substituent which may be possessed by ring A and ring B may for example be a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, a mono- or dialkylamino group, an optionally halogenated alkylthio group, etc.
A substituent which may be possessed favorably by ring A and ring B includes a halogen atom, an optionally substituted C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a mono- or di-C1-4 alkylamino group, an optionally halogenated C1-4 alkylthio group, etc.
Among those listed above, a halogen atom, an optionally substituted C1-4 alkyl group and an optionally halogenated C1-4 alkoxy group are employed preferably.
A substituent on ring A and ring B may be on any position capable of being substituted on the ring, and when two or more substituents are present, they may be same or different and the number of such substituents may be 1 to about 4. The number of the substituents is preferably 1 to about 3.
When each of ring A and ring B has a nitrogen atom, a quaternary ammonium salt may be formed together with an anion such as, for example, a halogen ion (such as Clxe2x88x92, Brxe2x88x92, Ixe2x88x92), sulfate ion, hydroxy ion, etc.
Each of ring A and ring B is preferably an optionally substituted benzene ring.
A substituent on an xe2x80x9coptionally substituted benzenexe2x80x9d means, for example, one exemplified above as a substituent on ring A and ring B.
A condensed ring formed whena substituent on ring A (or ring B) is bound to a position capable of being substituted on ring B (or ring A) and taken together with ring A, ring B and X2 described later may for example be fluorene, anthracene, dibenzofuran, dibenzopyrane, dibenzodioxane, carbazol, acridine, phenothiazine, etc., in detail a tricyclic condensed ring represented by Formula: 
wherein each of ring A and ring B has a meaning defined above, and x2 has a meaning defined later being preferred.
One exemplified more preferably is a tricyclic condensed ring represented by Formula: 
wherein each of ring A and ring B has a meaning defined above.
Group xe2x80x9cR1xe2x80x9d
Each R1 may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR2 (wherein R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group).
A xe2x80x9chydrocarbon groupxe2x80x9d in an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 may for example be an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and an aryl group, with an alkyl group, a cycloalkyl group and an aryl group, especially an alkyl group, being preferred.
An xe2x80x9calkyl groupxe2x80x9d is a straight or branched chain of 1 to 6 carbon atoms, preferably, a straight or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
An xe2x80x9calkenyl groupxe2x80x9d may for example be an alkenyl group having 2 to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl and the like, with an alkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl and isopropenyl being employed preferably.
An xe2x80x9calkynyl groupxe2x80x9d may for example be an alkynyl group having 2 to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl and the like, with an alkynyl group having 2 to 4 carbon atoms such as ethynyl, propynyl and isopropynyl being employed preferably.
A xe2x80x9ccycloalkyl groupxe2x80x9d may for example be a C3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., with a C3-6 cycloalkyl group such as cyclopropyl and cyclobutyl being employed preferably.
An xe2x80x9caryl groupxe2x80x9d may for example be an aryl group having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl, phenanthryl, etc., with an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl being employed preferably.
A xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d may for example be:
(i) a halogen atom (for example, fluorine, chlorine, bromine, iodine atoms, etc.);
(ii) an optionally substituted alkyl group;
(iii) a cycloalkyl group (for example, a C3-8 cycloalkyl group, etc. such as cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.);
(iv) an optionally substituted aryl group;
(v) an optionally halogenated alkoxy group (for example, a C1-6 alkoxy group, etc. which is substituted optionally with a halogen atom such as fluorine and chlorine atoms, etc., such as methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy groups, C3-8 cycloalkyloxy and heterocyclyloxy groups, etc.);
(vi) a nitro group;
(vii) a cyano group;
(viii) a hydroxy group;
(ix) an aryloxy group (for example, a C6-14 aryloxy group, etc. such as phenoxy and naphthyloxy groups, etc.);
(x) an aralkyloxy group (for example, a C6-14 aryl group-C1-4 alkyloxy group, etc. such as benzyloxy and phenethyloxy groups, etc.);
(xi) an optionally halogenated alkylthio group (for example, a C1-6 alkylthio group (especially C1-4 alkylthio group, etc.) which is substituted optionally with a halogen atom such as fluorine and chlorine, such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio groups);
(xii) an amino group;
(xiii) an amino group which is mono- or disubstituted by a formyl group or an optionally substituted alkyl group (for example, a mono- or di-C1-6 alkylamino group (especially mono- or di-C1-4 alkylamino group) such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino groups, etc., formylamino group, pyrimidinylmethylamino group, etc.);
(xiv) a cyclic amino group (for example, a 5- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms such as oxygen and sulfur atoms in addition to nitrogen atoms (for example, pyrrolidino, piperidino and morpholino groups, etc.);
(xv) an alkylcarbonylamino group (for example, a C1-6 alkylcarbonylamino group, etc. such as acetylamino, propionylamino and butyrylamino groups, etc.);
(xvi) an alkoxycarbonylamino group (for example, a C1-6 alkoxycarbonylamino group, etc. such as ethoxycarbonylamino group, etc.);
(xvii) an arylcarbonylamino group (for example, a C6-14 arylcarbonylamino group, etc. such as benzoylamino group, etc.);
(xviii) an acyloxy group (for example, a C1-3 acyloxy group, etc. such as formyloxy, acetoxy and propionyloxy groups, etc.);
(xvix) an aminocarbonyloxy group;
(xx) a mono- or dialkylaminocarbonyloxy group (for example, a mono- or di-C1-6 alkylaminocarbonyloxy group, etc. such as methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy and diethylaminocarbonyloxy groups, etc.);
(xxi) an alkylsulfonylamino group (for example, a C1-6 alkylsulfonylamino group, etc. such as methylsulfonylamino, ethylsulfonylamino and propylsulfonylamino groups, etc.);
(xxii) an alkoxycarbonyl group (for example, a C1-6 alkoxycarbonyl group, etc. such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl groups, etc.);
(xxiii) an aralkyloxycarbonyl group (for example, a C7-15 aralkyloxycarbonyl group, etc. such as benzyloxycarbonyl group, etc.);
(xxiv) an aryloxycarbonyl group (for example a C6-14 aryloxycarbonyl group, etc. such as phenoxycarbonyl group, etc.);
(xxv) a carboxyl group;
(xxvi) an alkylcarbonyl group (for example, a C1-6 alkylcarbonyl group, etc. such as methylcarbonyl, ethylcarbonyl and butylcarbonyl groups, etc.);
(xxvii) a cycloalkylcarbonyl group (for example, a C3-8 cycloalkylcarbonyl group, etc. such as cyclopentylcarbonyl and cyclohexylcarbonyl groups, etc.);
(xxviii) an arylcarbonyl group (for example, a C6-14 arylcarbonyl group, etc. such as benzoyl group, etc.);
(xxix) a carbamoyl group;
(xxx) a thiocarbamoyl group;
(xxxi) a mono- or dialkylcarbamoyl group (for example, a mono- or di-C1-6 alkylcarbamoyl group, etc. such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl and dibutylcarbamoyl groups, etc.);
(xxxii) an alkylsulfonyl group (for example, a C1-6 alkylsulfonyl group, etc. such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.);
(xxxiii) a cycloalkylsulfonyl group (for example, a C3-8 cycloalkylsulf onyl group, etc. such as cyclopentylsulfonyl and cyclohexylsulfonyl groups, etc.);
(xxxiv) an arylsulfonyl group (for example, a C6-14 arylsulfonyl group, etc. such as phenylsulfonyl and naphthylsulfonyl groups, etc.);
(xxxv) an aralkylsulfonyl group (for example a C7-15 aralkylsulfonyl group, etc. such as benzylsulfonyl group, etc.); and,
(xxxvi) an optionally substituted 5- or 6-membered heterocyclic group, etc.
An xe2x80x9coptionally substituted 5- or 6-membered heterocyclic groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbonxe2x80x9d represented by R1 may for example be a 5- or 6-membered aromatic heterocyclic group, a saturated or unsaturated 5- or 6-membered non-aromatic heterocyclic group, etc.
Such xe2x80x9c5- or 6-membered aromatic heterocyclic groupxe2x80x9d may for example be furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
A xe2x80x9c5- or 6-membered non-aromatic heterocyclic groupxe2x80x9d described above may for example be pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl, etc.
Such non-aromatic heterocyclic group may further be condensed with other aromatic or non-aromatic homocyclic or heterocyclic rings.
A xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted 5- or 6-membered heterocyclic groupxe2x80x9d represented as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbonxe2x80x9d may for example be one exemplified as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted homocyclic or heterocyclic ringxe2x80x9d represented by ring A and ring B described above.
In addition, a group represented by formula: 
wherein each symbol has a meaning defined above may also be exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
The number of the substituents on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 is 1 to about 5 (preferably 1 to 2), and when two or more substituents are present they may be same or different.
An xe2x80x9coptionally substituted alkyl groupxe2x80x9d described as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 may for example be an xe2x80x9coptionally substituted alkyl groupxe2x80x9d exemplified as a substituent possessed optionally by a xe2x80x9chomocyclic or heterocyclic ringxe2x80x9d represented by ring A and ring B described above.
An xe2x80x9caryl groupxe2x80x9d in an xe2x80x9coptionally substituted aryl groupxe2x80x9d described as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 may for example be an aryl group having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl and phenanthryl, etc., which an aryl having 6 to 10 carbon atoms such as phenyl and naphthyl being employed preferably.
A xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted aryl groupxe2x80x9d described as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 may for example be (i) a halogen atom such as fluorine and chlorine, etc., (ii) an optionally halogenated C1-4 alkyl group such as methyl, ethyl and trifluoromethyl group, etc., or (iii) a C1-4 alkoxy group, etc. such as methoxy and ethoxy groups, etc.
An xe2x80x9cacyl groupxe2x80x9d represented by R1 may for example be xe2x80x94(Cxe2x95x90O)xe2x80x94R6, xe2x80x94SO2xe2x80x94R6, xe2x80x94SOxe2x80x94R6, xe2x80x94(Cxe2x95x90O) NR6R27, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R6,xe2x80x94(cxe2x95x90S)Oxe2x80x94R6, xe2x80x94(Cxe2x95x90S)NR6R27, xe2x80x94(Pxe2x95x90O)(OR6)2, xe2x80x94(Pxe2x95x90O)(OR6)(O 27) (wherein R6 is a hydrogen atom or an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group, and R27 is a hydrogen atom or a lower alkyl group (for example, a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc., with a C1-3 alkyl group such as methyl, ethyl, propyl and isopropyl, etc. being preferred)), etc.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R6 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above.
A xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 may for example be an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an acyl group, etc.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d as a xe2x80x9ctubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino group represented by R6 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above.
An xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 may for example be (i) a hydroxy group, (ii) a C1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups, etc.), (iii) a C6-14 aryloxy group (for example, phenyloxy and naphthyloxy groups, etc.), (iv) a C1-6 alkylcarbonyloxy group (for example, formyloxy, acetoxy and propionyloxy groups, etc.), and (v) a C6-14 arylcarbonyloxy group (for example, benzyloxy and naphthylcarbonyloxy groups, etc.), etc., with a hydroxy group and a C1-6 alkoxy group (for example, methoxy, ethoxy, propoxy and isopropoxy groups, etc.) being preferred.
An xe2x80x9cacyl groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 may for example be xe2x80x94(Cxe2x95x90O)xe2x80x94R28, xe2x80x94SO2xe2x80x94R28, xe2x80x94SOxe2x80x94R28, xe2x80x94(Cxe2x95x90O)NR28R29, xe2x80x94(Cxe2x95x90O)Oxe2x80x94R28, xe2x80x94(Cxe2x95x90S)Oxe2x80x94R28, xe2x80x94(Cxe2x95x90S)NR28R29 (wherein R28 is a hydrogen atom or an optionally substituted hydrocarbon group, and R29 is a hydrogen atom or a lower alkyl group (for example, a C1-6 alkyl group, etc. such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc., with a C1-3 alkyl group such as methyl, ethyl, propyl and isopropyl, etc. being preferred)), etc.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R28 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above.
Each of xe2x80x9cC1-6 alkoxy groupxe2x80x9d, xe2x80x9cC6-14 aryloxy groupxe2x80x9d, xe2x80x9cC1-6 alkylcarbonyloxy groupxe2x80x9d and xe2x80x9cC6-14 arylcarbonyloxy groupxe2x80x9d exemplified as an xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 may further be substituted by one similar to a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above, and such substituent is preferably a halogen atom (for example, fluorine, chlorine and bromine, etc.).
An xe2x80x9coptionally substituted hydroxy groupxe2x80x9d represented by R6 described above may for example be one exemplified as an xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
Otherwise, R6 and R27 may be taken together to form a cyclic amino group (for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms such as oxygen and sulfur atoms in addition to nitrogen atoms (for example, pyrrolidino, piperidino and morpholino groups, etc.), etc.).
A xe2x80x9cheterocyclic groupxe2x80x9d in an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 may for example be an aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group containing as an ring member atom (ring atom), in addition to carbon atoms, at least one (preferably 1 to 4, more preferably 1 to 2) atom of 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
Such xe2x80x9caromatic heterocyclic groupxe2x80x9d may for example be 5- or 6-membered aromatic monocyclic heterocyclic group (for example furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, etc.), etc. and an 8- to 12-membered aromatic condensed heterocyclic group such as an aromatic condensed heterocyclic group (for example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolyl, quinoxanyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrenyl, indolydinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl, etc.) (preferably, a heterocyclic ring formed by condensing a 5- or 6-membered aromatic monocyclic heterocyclic group described above with a benzene ring, or a heterocyclic ring formed by condensing the same or different 2 heterocyclic rings of 5- or 6-membered aromatic monocyclic heterocyclic groups described above).
A xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d described above may for example be a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group, etc. such as oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
A xe2x80x9csubstituentxe2x80x9d on are xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 may for example be one exemplified as a substituent which may be possessed by a xe2x80x9chomocyclic or heterocyclic ringxe2x80x9d represented by ring A and ring B, as well as a group represented by Y (Y has a meaning defined above) in Formula (I) shown above and a group represented by Formula: 
wherein each symbol has a meaning defined above.
A xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 may be on any position capable of being substituted on a ring, and when two or more substituents are present then they may be same or different and the number of them may be 1 to about 3. The number of the substituents is preferably 1 to about 2.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R2 in xe2x80x9cSR2 (wherein R is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group)xe2x80x9d represented by R1 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above.
An xe2x80x9cacyl groupxe2x80x9d represented by R2 in xe2x80x9cSR2 (wherein R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group)xe2x80x9d represented by R1 may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by RX described above.
An xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R2 in xe2x80x9cSR2 (wherein R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group)xe2x80x9d represented by Rlmayfor example be one exemplified as an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 described above.
Those employed preferably as R1 may for example be a hydrogen atom, an optionally substituted lower alkyl group, xe2x80x94(Cxe2x95x90O)xe2x80x94R6 (wherein R6 has a meaning defined above) or SR2 (wherein R2 has a meaning defined above).
An xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d as a preferred example of R1 may for example be:
(a) a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl;
(b) ahalogenated C1-6 alkyl group (for example, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl and perfluorobutyl groups, etc.);
(c) an amino group-substituted C1-6 alkyl group (for example, aminomethyl and 2-aminoethyl groups, etc.);
(d) amono- or di-C1-6 alkylamino group-substituted C1-6 alkyl group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);
(e) a carboxyl group-substituted C1-6 alkyl group (for example, carboxymethyl and carboxyethyl groups, etc.);
(f) a C1-6 alkoxycarbonyl group-substituted C1-6 alkyl group (for example, methoxycarbonylethyl, ethoxycarbonylethyl and t-butoxycarbonylmethyl groups, etc.);
(g) a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.);
(h) a C6-14 aryl group-substituted C1-6 alkyl group (for example, benzyl, etc.);
(i) a C1-6 alkoxy group-substituted C1-6 alkyl group (for example, methoxymethyl, methoxyethyl, etc.); or,
(j) a C7-15 aralkyloxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl, etc.), etc. More preferably, R1 is (1) a hydrogen atom, (2) a C1-6 alkyl group substituted optionally with [1] a C1-6 alkoxycarbonyl group (especially, ethoxycarbonyl, t-butoxycarbonyl, etc.), or with [2] a C6-14 aryl group (especially phenyl, etc.), or, (3) xe2x80x94(Cxe2x95x90O)xe2x80x94R6a (wherein R6a is a C1-6 alkyl group (especially methyl, etc.) or a C6-14 aryl group (especially phenyl, etc.), etc.), etc.
Furthermore, a group represented by Formula: 
wherein each symbol has a meaning defined above, or by Formula: 
wherein each symbol has a meaning defined above may also be mentioned to be preferable as R1.
Group xe2x80x9cX1xe2x80x9d
X1 is a bond, an optionally substituted divalent C1-3 aliphatic hydrocarbon group or xe2x80x94NR3xe2x80x94 (wherein R3 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group).
A xe2x80x9cdivalent C1-3 aliphatic hydrocarbon groupxe2x80x9d in an xe2x80x9coptionally substituted divalent C1-3 aliphatic hydrocarbon groupxe2x80x9d is a group obtained by removing (2 in total of) hydrogen atoms each one of which is binding to a same or different carbon atoms in a saturated or unsaturated C1-3 aliphatic hydrocarbon. Those exemplified typically are:
(i) a C1-3 alkylene group (for example, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, etc.);
(ii) a C2-3 alkenylene group (forexample xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, etc.);
(iii) a C2-3 alkynylene group (for example,
xe2x80x94Cxe2x89xa1Cxe2x80x94 xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94
etc.).
Among those listed above, a C1-3 alkylene group (for example, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, etc.) are employed frequently. Preferably, xe2x80x94CH2xe2x80x94 is employed.
A xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted divalent C1-3 aliphatic hydrocarbon groupxe2x80x9d represented by X1 may for example be one exemplified as a xe2x80x9csubstituent xe2x80x9d on an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above (provided that a group represented by Formula: 
wherein each symbol has a meaning defined above as a substituent on an optionally substituted hydrocarbon group represented by R1 is excluded from the substituents on an xe2x80x9coptionally substituted divalent C1-3 aliphatic hydrocarbon groupxe2x80x9d), as well as an oxo group and a thioxo group, etc.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by xe2x80x9cR3xe2x80x9d in xe2x80x9cxe2x80x94NR3xe2x80x94xe2x80x9d represented by X1 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above (provided that a group represented by Formula: 
wherein each symbol has a meaning defined above as a substituent a hydrocarbon group represented by R1 is excluded from the substituents on a hydrocarbon group represented by R1).
An xe2x80x9cacyl groupxe2x80x9d represented by xe2x80x9cR3xe2x80x9d in xe2x80x9cxe2x80x94NR3xe2x80x94xe2x80x9d represented by X1 may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by R1 described above.
X1 is preferably an optionally substituted methylene group. A xe2x80x9csubstituentxe2x80x9d on such xe2x80x9coptionally substituted methylene groupxe2x80x9d may for example be one exemplified as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted divalent C1-3 aliphatic hydrocarbon groupxe2x80x9d represented by X1.
A particularly preferred X1 is an unsubstituted methylene group.
Group xe2x80x9cX2xe2x80x9d
X2 is a bond, an optionally substituted divalent C1-3 aliphatic hydrocarbon group, xe2x80x94NR4 xe2x80x94 (wherein R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), xe2x80x94Oxe2x80x94 or xe2x80x94S(O)pxe2x80x94 (wherein p is 0, 1 or 2).
An xe2x80x9coptionally substituted divalent C1-3 aliphatic hydrocarbon groupxe2x80x9d represented by X2 may for example be one exemplified as an xe2x80x9coptionally substituted divalent C1-3 aliphatic hydrocarbon groupxe2x80x9d represented by X1 described above.
An xe2x80x9cacyl groupxe2x80x9d represented by xe2x80x9cR4xe2x80x9d in xe2x80x9cxe2x80x94NR4xe2x80x94represented by X2 may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by R1 described above.
X2 is preferably xe2x80x94Oxe2x80x94.
Group xe2x80x9cYxe2x80x9d
Each Y may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR5 (wherein R5 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R3 described above.
A xe2x80x9chalogen atomxe2x80x9d represented by Y may for example be fluorine, chlorine, bromine, iodine, etc.
An xe2x80x9cacyl groupxe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by R1 described above.
An xe2x80x9coptionally substituted hydroxy groupxe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
An xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d as xe2x80x9cR5 in xe2x80x9cSR5xe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R3 described above.
An xe2x80x9cacyl groupxe2x80x9d as xe2x80x9cR5xe2x80x9d in xe2x80x9cSR5xe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by R1 described above.
An xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as xe2x80x9cR5xe2x80x9d in xe2x80x9cSR5xe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 described above (provided that, among the examples of a xe2x80x9csubstituentxe2x80x9d in an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 described above, a group represented by Y (wherein Y has a meaning defined above)and a group represented by Formula: 
wherein each symbol has a meaning defined above are excluded from the substituents on an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R5).
A substituent on an xe2x80x9coptionally substituted imino groupxe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d or an xe2x80x9cacyl groupxe2x80x9d represented by R4.
Those employed preferably as Y may for example be a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR12 (wherein R12 is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group) or an oxo group, etc.
An xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d described above as a preferred example of Y may for example be:
(a) a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, etc.;
(b) a halogenated C1-6 alkyl group (for example, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl and perfluorobutyl groups, etc.);
(c) an amino group-substituted C1-6 alkyl group (for example, aminomethyl and 2-aminoethyl groups, etc.);
(d) a mono- or di-C1-6 alkylamino group-substituted C1-6 alkyl group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);
(e) a carboxyl group-substituted C1-6 alkyl group (for example, carboxymethyl and carboxyethyl groups, etc.);
(f) a C1-6 alkoxycarbonyl group-substituted C1-6 alkyl group (for example, methoxycarbonylethyl, ethoxycarbonylethyl and t-butoxycarbonylmethyl groups);
(g) a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.);
(h) a C6-14 aryl group-substituted C1-6 alkyl group (for example, benzyl, etc.);
(i) a C1-6 alkoxy group-substituted C1-6 alkyl group (for example, methoxymethyl, methoxyethyl, etc.); or,
(j) a C7-15 aralkyloxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl, etc.), etc.
An xe2x80x9coptionally substituted hydroxy groupxe2x80x9d described above as a preferred example of Y may for example be one exemplified as an xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
An xe2x80x9coptional substituted amino groupxe2x80x9d described above as a preferred example of Y may for example be one exemplified as an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
An xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d as xe2x80x9cR12xe2x80x9d in xe2x80x9cSR12xe2x80x9d described above as a preferred example of Y may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R3 described above.
An xe2x80x9cacyl groupxe2x80x9d as xe2x80x9cR12xe2x80x9d in xe2x80x9cSR12xe2x80x9d represented as Y may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by R1 described above.
An xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as xe2x80x9cR12xe2x80x9d in xe2x80x9cSR12xe2x80x9d represented by Y may for example be one exemplified as an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 described above (provided that among the examples of a xe2x80x9csubstituentxe2x80x9d in an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 described above, a group represented by Y (wherein Y has a meaning defined above) and a group represented by Formula: 
wherein each symbol has a meaning defined above are excluded from the substituents on an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R12).
More preferably, Y may for example be an unsubstituted C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.), an alkoxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl and methoxymethyl groups, etc.) as well as an oxo group.
Number xe2x80x9cmxe2x80x9d
Each m may be same or different and is 0 or 1. m is preferably 0.
Number xe2x80x9cnxe2x80x9d
Each n is an integer of 1 to 3. n is preferably 1 to 2, especially 1.
Numbers xe2x80x9cq1 and q2xe2x80x9d
q1 is an integer of 1 to 2n+4, q2 is an integer of 0 to 2n+3, and the sum of q1 and q2 is 2n+4.
Preferably q1 is 1.
Partial structure of compound represented by Formula [I]
A preferred group represented by Formula 
which is a partial structure of Formula [I] shown above may for example be a group represented by Formula: 
wherein each of R7 to R11 may be same or different and each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted hydroxy group, an optionally substituted amino group or SR12 (wherein R12 has a meaning defined above) and each of other symbols has a meaning defined above.
An xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d represented by each of R7 to R11xe2x80x9d may for example be:
(a) a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, etc.;
(b) a halogenated C1-6 alkyl group (for example, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl and perfluorobutyl groups, etc.);
(c) an amino group-substituted C1-6 alkyl group (for example, aminomethyl and 2-aminoethyl groups, etc.);
(d) a mono- or di-C1-6 alkylamino group-substituted C1-6 alkyl group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);
(e) a carboxyl group-substituted C1-6 alkyl group (for example, carboxymethyl and carboxyethyl groups, etc.);
(f) a C1-6 alkoxycarbonyl group-substituted C1-6 alkyl group (for example, methoxycarbonylethyl, ethoxycarbonylethyl and t-butoxycarbonylmethyl groups, etc.);
(g) a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.);
(h) a C6-14 aryl group-substituted C1-6 alkyl group (for example, benzyl, etc.);
(i) a C1-6 alkoxy group-substituted C1-6 alkyl group (for example, methoxymethyl, methoxyethyl, etc.); or,
(j) a C7-15 aralkyloxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl, etc.), etc.
An xe2x80x9coptionally substituted hydroxy groupxe2x80x9d represented by each of R7 to R11 may for example be one exemplified as an xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
An xe2x80x9coptionally substituted amino groupxe2x80x9d represented by each of R7 to R11 may for example be one exemplified as an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
More preferably, each of R7 to R11 may for example be an unsubstituted C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.), an alkoxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl and methoxymethyl groups, etc.) as well as an oxo group.
A most preferred group represented by Formula: 
which is a partial structure of Formula [I] shown above may for example be a group represented by Formula: 
wherein each of R13 to R25 may be same or different and each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted hydroxy group, an optionally substituted amino group or SR12 (wherein R12 has a meaning defined above).
An xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d represented by each of R13 to R25 may for example be:
(a) a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, etc.;
(b) a halogenated C1-6 alkyl group (for example, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl and perfluorobutyl groups, etc.);
(c) an amino group-substituted C1-6 alkyl group (for example, aminomethyl and 2-aminoethyl groups, etc.);
(d) a mono- or di-C1-6 alkylamino group-substituted C1-6 alkyl group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);
(e) a carboxyl group-substituted C1-6 alkyl group (for example, carboxymethyl and carboxyethyl groups, etc.);
(f) a C1-6 alkoxycarbonyl group-substituted C1-6 alkyl group (for example, methoxycarbonylethyl, ethoxycarbonylethyl and t-butoxycarbonylmethyl groups, etc.);
(g) a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.);
(h) a C6-14 aryl group-substituted C1-6 alkyl group (for example, benzyl, etc.);
(i) a C1-6 alkoxy group-substituted C1-6 alkyl group (for example, methoxymethyl, methoxyethyl, etc.); or,
(j) a C7-15 aralkyloxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl, etc.), etc.
An xe2x80x9coptionally substituted hydroxy groupxe2x80x9d represented by each of R13 to R25 may for example be one exemplified as an xe2x80x9coptionally substituted hydroxy groupxe2x80x9d as a xe2x80x9csubstituentxe2x80x9d on an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
An xe2x80x9coptionally substituted amino groupxe2x80x9d represented by each of R13 to R25 may for example be one exemplified as an xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R6 described above.
More preferably, each of R13 to R25 may for example be an unsubstituted C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), a hydroxy group-substituted C1-6 alkyl group (for example, hydroxymethyl and hydroxyethyl groups, etc.), an alkoxy group-substituted C1-6 alkyl group (for example, benzyloxymethyl and methoxymethyl groups, etc.) as well as an oxo group.
Among the groups represented by Formula: 
wherein each symbol has a meaning defined above, each of which is exemplified as a preferred group represented by Formula: 
which is a partial structure of Formula [I] shown above, one preferred particularly may for example be a group represented by Formula: 
wherein each symbol has a meaning defined above.
Preferred examples of a compound represented by Formula [I] may for example be the compounds represented later by Formula [Ia], [Ib], [Ic], [Id], [Ie], [If], [Ig], [Ih], [Ii], [XXXIV] and [XXXVII].
One preferred particularly is a compound represented by Formula [I] wherein both of ring A and ring B are benzene rings, R1 is an acyl group, X1 is methylene, X2 is an oxygen atom and n is 1.
Optical isomers of compound represented by Formula [I]
While a compound represented by Formula [I] or a salt thereof can exist as an optical isomer when it contains an asymmetric carbon in its structure, a preferable optical isomer may for example be a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof.
A method for producing compound (I) according to the invention or a salt thereof is discussed below.
Compound (I) according to the invention or a salt thereof can be produced by methods (A) to (N) described below.
(Method A) A compound represented by Formula: 
wherein q1a is an integer of 1 to 2n+2, q2a is an integer of 0 to 2n+1, and the sum of q1a and q2a is 2n+2 and each of other symbols has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein q1a is an integer of 1 to 2n+2, q2a is an integer of 0 to 2n+1, and the sum of q1a and q2a is 2n+2 or a salt thereof or with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof.
In this reaction, one mole of compound [II] or a salt thereof is reacted usually with 1 to 5 moles, preferably 1 to 3 moles of compound [III] or a salt thereof or compound [IV] or a salt thereof.
A reaction solvent is an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an organic acid such as acetic acid, etc., an organic acid anhydride such as acetic anhydride, etc. and an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc.
This reaction is conducted usually under a dehydrating condition. The addition of an acid in this reaction allows the reaction to proceed advantageously. Such acid is preferably an inorganic acid such as hydrochloric acid and sulfuric acid, etc. and an organic acid such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid and maleic acid, etc. While the amount of an acid employed may vary depending on the types of the compound and the solvent employed as well as other reaction conditions, it is usually 0.01 to 1 mole, preferably 0.05 to 0.1 mole per 1 mole of the compound.
The reaction temperature is usually 0 to 200xc2x0 C., preferably 50 to 150xc2x0 C.
The reaction time is usually 30 minutes to 48 hours, preferably 1 to 24 hours.
Compound [II] is produced for example by method N described below, and compound [III] or [IV] is commercially available or may be a sulfur-substituted acid anhydride and a dicarboxylic acid produced for example in method D described below.
(Method B) Compound (I) or a salt thereof according to the invention can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof or with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to produce a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof or a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof, followed by reacting a compound represented by Formula [VII] or [VIII] shown above or a salt thereof with a compound represented by R1SH (wherein R1 has a meaning defined above) or a salt thereof.
In order to react a compound represented by Formula [II] or a salt thereof with a compound represented by Formula [V] or [VI] or a salt thereof to form a compound represented by Formula [VII] or [VIII] or a salt thereof, a method similar to (method A) described above may be employed.
In a reaction to produce a compound represented by Formula [I] or a salt thereof from a compound represented by Formula [VII] or [VIII] or a salt thereof, 1 to 5 moles, preferably 1 to 3 moles of a compound represented by R1SH (wherein R1 has a meaning defined above) is used per 1 mole of a compound represented by Formula [VII] or [VIII] or a salt thereof.
R1SH may for example be an inorganic sulfide such as hydrogen sulfide, sodium hydrogen sulfide and sodium sulfide, etc. and their salts, an organic sulfur-containing acid such as thioacetic acid and thiobenzoic acid, etc. and their salts, an aliphatic mercaptan such as methylmercaptan, benzylmercaptan, triphenylmethylmercaptan and 3-mercaptopropionic acid derivatives, etc., an aromatic mercaptan such as thiophenol and a thiourea.
A reaction solvent is an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
The addition of a base in this reaction allows the reaction to proceed advantageously. Such base is an inorganic base (alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, alkoxide such as sodium methoxide and sodium ethoxide, etc.) and an organic base (amine such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amine such as pyridine, etc.), etc.
Instead of using a base in this reaction, a compound represented by R1SH (wherein R1 has a meaning defined above) or a salt thereof may be converted for example into an alkaline metal salt or an alkaline earth metal salt, which may then be reacted with a compound represented by Formula [VII] or [VIII] or a salt thereof.
While the amount of a base employed may vary depending on the types of the compound and the solvent employed as well as other reaction conditions, it is usually 1 to 10 moles, preferably 1 to 5 moles per 1 mole of a compound represented by R1SH (wherein R1 has a meaning defined above) or a salt thereof. The reaction temperature is usually xe2x88x9250 to 200xc2x0 C., preferably xe2x88x9220 to 100xc2x0 C. The reaction time may vary depending on the type of the compound and the reaction temperature, and is usually 1 to 72 hours, preferably 1 to 24 hours.
(Method C) A compound represented by Formula: 
wherein q2b is 2n+3 and each of other symbols has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with an oxidizing agent.
An oxidizing agent employed in this reaction may be an ordinary disulfide bond-forming reagent found in xe2x80x9cSHINJIKKENKAGAKUKOZAxe2x80x9d, Vol. 15, Oxidation and Reduction (MARUZEN), for example, a halogen such as chlorine, bromine and iodine, etc., an N-halogen carboxylimide such as N-chlorosuccinimide, etc. or a sulfonamide, a metallic oxidizer such as a chromic acid, lead tetraacetate, potassium permanganate and iron chloride, etc., an organic peroxide such as m-chloroperbenzoic acid and peracetic acid, etc. or hydrogen peroxide or an air oxidation, etc.
In this reaction, usually 1 to 5 moles, preferably 1 to 2 moles of an oxidizing agent is employed per 1 mole of compound [IX] or a salt thereof.
A reaction solvent is an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
The addition of a base in this reaction allows the reaction to proceed advantageously. Such base is an inorganic base (alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., halide such as sodium iodide and potassium iodide, etc., alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, alkoxide such as sodium methoxide and sodium ethoxide, etc.) and an organic base (amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., cyclic amine such as pyridine, etc.). While the amount of a base employed may vary depending on the types of the compound and the solvent employed as well as other reaction conditions, it is usually 0.1 to 20 moles, preferably 1 to 2 moles per 1 mole of compound [IX] or a salt thereof.
The reaction temperature is usually xe2x88x9220 to 200xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is usually 1 minute to 24 hours, preferably 1 minute to 5 hours.
(Method D) A compound represented by Formula: 
wherein q1c is an integer of 1 to 2n+2, q2c is an integer of 0 to 2n+1, and the sum of q1c and q2c is 2n+2 which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof.
In this reaction, compound [X] or a salt thereof is first reacted with various acid anhydrides or acid halides to form a corresponding acid anhydride. A reagent employed is an acid anhydride or an acid halide of an ordinary organic acid such as acetic acid and benzoic acid, etc.
This reaction employs 1 to 50 moles of a reagent per 1 mole of compound [X] or a salt thereof. While the reaction solvent is an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an organic acid such as acetic acid, etc., a nitrile such as acetonitrile, etc. and an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc., it May be an acid anhydride itself employed as a reagent. While the reaction temperature may vary depending on compound [X] or a salt thereof employed as well as other reaction conditions, it is 0 to 200xc2x0 C., preferably 20 to 150xc2x0 C. The reaction time is 30 minutes to 24 hours, preferably 1 to 10 hours. An acid anhydride thus obtained and compound[II] or a salt thereof are subjected to a method similar to that in (Method A) described above to produce compound [Ic] or a salt thereof.
Among compounds represented as compounds [Ic], one wherein R1 is other than an acyl group can be hydrolyzed with an acid or a base to produce a compound wherein R1 is H.
An acid which may be employed may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and a base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., ammonia, an organic amine such as methylamine and ethylamine, etc.
This reaction is conducted in a 20 to 50 volumes of an aqueous solution of an inorganic acid described above (usually at 10 to 30%) per 1 g of a compound among compounds [Ic] wherein R1 is an acyl group, or in an aqueous solution containing 3 to 10 moles of a base described above per 1 mole of a compound among compounds [Ic] wherein R1 is an acyl group. In view of the solubility of a compound, the reaction may be performed in an aqueous solution described above which is supplemented with an organic solvent, or the reaction may be performed in an organic solvent. An organic solvent which may be employed is an alcohol such as methanol clnd ethanol, etc., an organic acid such as acetic acid, etc., an ether such as dioxane and tetrahydrofuran, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on the compound among compounds [Ic] wherein R1 is an acyl group as well as other conditions, it is usually 0 to 200xc2x0 C., preferably 20 to 150xc2x0 C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.
Alternatively, a compound represented by Formula (X) shown above or a salt thereof can be produced also by reacting a compound represented by Formula: 
wherein L1 is a leaving group, each Ra may be same or different and is an optionally substituted hydrocarbon group, and Y has a meaning defined above or a salt thereof with a sulfur-containing nucleophilic agent followed by a hydrolysis.
A leaving group represented by L1 in compound [XI] may for example be hydroxy, a halogen atom (for example, chlorine, bromine and iodine, etc.), a substituted sulfonyloxy (for example, methanesulfonyloxy and p-toluenesulfonyloxy, etc.), an acyloxy (such as acetoxy and benzoyloxy, etc.), and an oxy group substituted by a heterocyclic ring or an aryl group (such as succinimide, benzotriazole, quinoline and 4-nitrophenyl, etc.).
An optionally substituted hydrocarbon group represented by R6 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above, with a C1-4 alkyl group such as methyl, ethyl and propyl, etc. being employed preferably.
A sulfur-containing nucleophilic agent is an inorganic sulfide such as hydrogen sulfide, sodium hydrogen sulfide and sodium sulfide, etc., an organic sulfur-containing acid such as thioacetic acid and thiobenzoic acid, etc. as well as their salts, a mercaptan such as benzylmercaptan, triphenylmethylmercaptan and 3-mercaptopropionic acid derivatives, etc. and a thiourea. A base may for example be an inorganic base (alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, alkoxide such as sodium methoxide and sodium ethoxide, etc.) and an organic base (amine such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amine such as pyridine, etc.).
In this reaction, 1 to 5 moles, preferably 1 to 3 moles of an sulfur-containing nucleophilic agent is employed per 1 mole of compound [XI] or a salt thereof. A base is employed also in an amount of 1 to 5 moles, preferably 1 to 3 moles.
A reaction solvent is an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on the compound employed as well as other conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 150xc2x0 C. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 6 hours.
A sulfur-substituted product thus obtained is hydrolyzed with an acid or a base to yield compound [X] or a salt thereof.
An acid which may be employed is an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and a base is an inorganic base (alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc.).
This reaction is conducted in a 20 to 50 volumes of an aqueous solution of an inorganic acid described above (usually at 10 to 30%) per 1 g of a sulfur-substituted product, or in an aqueous solution containing 3 to 10 moles of a base described above per 1 mole of a sulfur-substituted product. In view of the solubility of a compound, the reaction may be performed in an aqueous solution described above which is supplemented with an organic solvent. An organic solvent which may be employed is an alcohol such as methanol and ethanol, etc., an organic acid such as acetic acid, etc., an ether such as dioxane and tetrahydrofuran, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on the sulfur-substituted product employed as well as other conditions, it is 0 to 200xc2x0 C., preferably 20 to 150xc2x0 C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.
Compound [XI] may be a commercially available halogenated dicarboxylic acid derivative, a product obtained from a corresponding aminodicarboxylic acid derivative by substituting an amino group with a halogen according to a method known in a literature such as Heterocycles, 24(5), 1331 (1986) or Journal of Organic Chemistry, 58(5), 1159 (1993), etc., or a product obtained from a corresponding hydroxy form by converting into an appropriate leaving group according to a method known in a literature such as an acylation or alkylation described for example in Organic Functional Group Preparations (Academic Press).
(Method E) A compound represented by Formula: 
wherein q2d is 0 to 2 and each of other symbols has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof in the presence of a base.
In this reaction, 1 to 5 moles, preferably 1 to 3 moles of a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof and 1 to 5 moles, preferably 1 to 3 moles of a base are employed per 1 mole of Compound [XII] or a salt thereof. A compound represented by R1SH wherein R1 has a meaning defined above which is employed may for example be an inorganic sulfide such as hydrogen sulfide, sodium hydrogen sulfide and sodium sulfide, etc., an aliphatic mercaptan such as methylmercaptan, a ethylmercaptan and mercaptopropionic acid derivatives, etc., an organic sulfur-containing acid such as thioacetic acid and thiobenzoic acid, etc., an aromatic mercaptan such as thiophenol, etc. and a thiourea, etc.
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
A reaction solvent which may be employed is an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc. Instead of using a base in this reaction, a compound represented by R1SH may be converted for example into an alkaline metal salt or an alkaline earth metal salt, which may then be reacted with compound [XII] or a salt thereof.
While the reaction temperature may vary depending on compound [XII] or a salt thereof employed as well as other reaction conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 150xc2x0 C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 6 hours.
A compound represented by Formula [XII] or a salt thereof may be produced also for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to form an amide followed by a hydrolysis and an imidation.
In this reaction, compound [XIII] or a salt thereof is first condensed with compound [II] or a salt thereof to form an amide.
This process may be in accordance with a known amidation such as a method described in xe2x80x9cJIKKENKAGAKUKOZAxe2x80x9d, Vol.22, Organic Synthesis IV (MARUZEN). A condensing agent may for example be dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate (DEPC) and diphenylphosphorylazide (DPPA), etc.
When using such a condensing agent, an ordinary solvent (for example, ethers, esters, hydrocarbons, amides and sulfoxides, etc. including tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, N,N-dimethylformamide, dimethylsulfoxide, etc.) is employed.
This reaction may be promoted in the presence of a base at a temperature of xe2x88x9210 to 100xc2x0 C., preferably 0 to 60xc2x0 C.
The reaction time is usually 30 minutes to 96 hours, preferably 1 to 72 hours. The amount of compound [II] or a salt thereof and a condensing agent employed is 1 to 5 moles, preferably 1 to 3 moles per 1 mole of compound [XIII] or a salt thereof.
A base may for example be an alkylamine such as triethylamine, etc. and a cyclic amine such as N-methylmorpholine and pyridine, etc., and is used in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1 mole of compound [XIII] or a salt thereof.
An ester thus obtained can be hydrolyzed to obtain a carboxylic acid. A hydrolysis may be effected using an acid or a base.
An acid which may be employed may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, and a base may for example be an inorganic base (alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc.).
This reaction is conducted in a 20 to 50 volumes of an aqueous solution of an inorganic acid described above (usually at 10 to 30%) per 1 g of an ester, or in an aqueous solution containing 3 to 10 moles of a base described above per 1 mole of an ester. In view of the solubility of a compound, the reaction may be performed in an aqueous solution described above which is supplemented with an organic solvent. An organic solvent which may be employed is an alcohol such as methanol and ethanol, etc., an organic acid such as acetic acid, etc., an ether such as dioxane and tetrahydrofuran, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide, etc. and N,N-dimethylacetamide and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on the ester employed as well as other conditions, it is 0 to 200xc2x0 C., preferably 20 to 150xc2x0 C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.
A carboxylic acid thus obtained can be condensed to yield compound [XII] or a salt thereof.
This reaction employs 10 to 50 volumes of a condensing agent as a reaction solvent per 1 g of a carboxylic acid. A condensing agent is an anhydride of an ordinary organic acid such as acetic anhydride and benzoic anhydride, etc. The addition of a base in this reaction allows the reaction to proceed advantageously.
A base which may be employed is preferably an alkaline metal salt of an organic acid corresponding to a condensing agent employed such as sodium acetate and potassium acetate. The amount is 0.1 to 1 mole based on a carboxylic acid.
While the reaction temperature may vary depending on the carboxylic acid employed as well as other conditions, it is 20 to 200xc2x0 C., preferably 50 to 150xc2x0 C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 5 hours.
As compound [VIII], a commercially available epoxysuccinic acid derivative is mainly employed.
(Method F) A compound represented by Formula: 
wherein q2e is 2n+1 and each of other symbols has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by subjecting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to a method similar to that in method C described above in the presence of a base.
A compound represented by Formula (XIV) or a salt thereof can be produced also by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to form an amide followed by reacting with a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof followed by an amidation.
In this amidation, 1 mole of compound [XV] or a salt thereof is reacted with 1 to 5 moles, preferably 1 to 2 moles of compound [II] or a salt thereof.
A reaction solvent may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on compound [XV] or a salt thereof as well as other conditions, it is xe2x88x9220 to 100xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is 5 minutes to 5 hours, preferably 5 minutes to 1 hour.
An amide thus obtained can be converted into an adduct by a method similar to that in (Method B) described above, and then condensed by a method similar to that in (Method E), whereby producing compound [XIV] or a salt thereof.
As compound [XV], a commercially available itaconic anhydride derivative is mainly employed.
(Method G) Compound (I) according to the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein L2 is a leaving group and each of other symbols has a meaning defined above or a salt thereof with a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof in the presence of a base.
A leaving group represented by L2 described above may for example be one exemplified as a leaving group as represented by L1 described above.
A compound represented by Formula (XVI) or a salt thereof can be produced for example from a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof.
Thus, compound [XVI] or a salt thereof can be produced by decarboxylating compound [XVII] or a salt thereof and then reacting a dicarbonyl compound thus formed in situ with a nucleophilic agent or a reducing agent to form a hydroxy product which is then converted into a leaving group.
A decarboxylation is performed in 1 to 100 volumes, preferably 20 to 50 volumes of a solvent per 1 g of compound [XVII]. While a solvent which may preferably be employed is a nitrile such as acetonitrile, etc., those also employed are an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc., a sulfoxide such as dimethylsulfoxide, etc. as well as water.
While the reaction temperature may vary depending on compound [XVII] or a salt thereof employed as well as other conditions, it is 0 to 200xc2x0 C., preferably 20 to 150xc2x0 C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 1 hour.
In a nucleophilic reaction and a reducing reaction, a nucleophilic agent or a reducing agent is employed in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1 mole of compound [XVII] or a salt thereof. A nucleophilic agent may be an organic metal reagent such as organic lithium, organic zinc, organic aluminum, Grignard reagent, etc. While a reducing agent may preferably be a metal hydride such as sodium borohydride as lithium aluminum hydride, etc., it may be a reagent capable of reducing a ketone compound to an alcohol, such as one described in xe2x80x9cSHINJIKKENKAGAKUKOZAxe2x80x9d, Vol.15, Oxidation and Reduction (MARUZEN).
A solvent which may be employed may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is xe2x88x92100 to 200xc2x0 C., preferably xe2x88x9278 to 100xc2x0 C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 10 hours.
A resultant hydroxy product can be converted into any of various leaving groups to produce compound [XVI]. Such leaving group may for example be a halogen atom (for example, chlorine, bromine and iodine, etc.), a substituted sulfonyloxy (for example, methanesulfonyloxy and p-toluenesulfonyloxy, etc.), an acyloxy (for example, acetoxy and benzoyloxy, etc.) and an oxy group which is substituted with a heterocyclic or aryl group (such as succinimide, benzotriazole, quinoline and 4-nitrophenyl, etc.), etc.
A halogen atom may for example be a halide of an inorganic acid, such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride, etc. and a halogenated hydrogen acid such as hydrochloric acid and hydrobromic acid, etc. Other leaving groups can be produced by known methods such as those described in method D for producing compound [XI].
For example, a latter reaction employing an acylation employs 1 to 5 moles, preferably 1 to 2 moles of a corresponding halide and 1 to 5 moles, preferably 1 to 3 moles of a base per 1 mole of a hydroxy product or a salt thereof. Some base, such as pyridine, can serve also as a solvent.
A solvent may for example be an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
While the reaction temperature may vary depending on the substrate employed as well as other conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.
A resultant compound can be subjected to a method similar to that in (Method D) described above to react with any of various sulfur-containing nucleophilic agents to produce compound [I] wherein R1 is not H or a salt thereof and also to be deprotected to produce compound [I] wherein R1 is H or a salt thereof.
Alternatively, a compound represented by Formula (XVII) or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof, or with a compound represented by Formula: 
wherein X1 is a halogen atom and each of other symbols has a meaning defined above or a salt thereof to form an amide, which is then subjected to a treatment with a base.
A halogen atom represented by X1 may for example be fluorine, chlorine, bromine and iodine, etc.
In this reaction, compound [XVIII] or a salt thereof can be condensed with compound [XIX] or a salt thereof using a condensing agent or its halide [XX] or a salt thereof can be reacted in the presence of a base to form an amide. The former reaction can be performed similarly to (Method E) described above.
The latter reaction employs 1 to 5 moles, preferably 1 to 2 moles of compound [XX] or a salt thereof per 1 mole of compound [XVIII] or a salt thereof. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. The amount of a base employed is I to 10 moles, preferably 1 to 5 moles per 1 moles of compound [XVIII] or a salt thereof. Some base, such as pyridine, can serve also as a solvent.
A solvent may for example be an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc. While the reaction temperature may vary depending on compound [XVIII] or a salt thereof employed as well as other conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
A resultant amide can be subjected to a treatment with a base to produce compound [XVII] or a salt thereof.
This reaction employs 1 to 3 moles, preferably 1 to 2 moles of a base per 1 mole of an amide. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc. A solvent which may be employed may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc. While the reaction temperature may vary depending on the amide employed as well as other conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is 5 minutes to 48 hours, preferably 10 minutes to 5 hours.
Alternatively, a compound represented by Formula (XVIII) or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof.
Compound [XVIII] or a salt thereof can be produced from compound [XXI] or a salt thereof and a carbonyl compound [XXII] by an in situ production of an imine which is then reduced by an appropriate reducing agent.
A reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
In this reaction, 1 to 5 moles, preferably 1 to 2 moles of carbonyl compound [XXII] and 0.5 to 10 moles, preferably 0.5 to 3 moles of a reducing agent per 1 mole of compound [XXI] or a salt thereof. A reaction solvent may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
When producing an imine, a dehydrating condition using a molecular sieve or an addition of an acid serves to promote the reaction. An acid employed here is preferably acetic acid and trifluoroacetic acid, etc. While the reaction temperature in this imine production may vary depending on compound [XXI] or a salt thereof as well as other conditions, it is 0 to 200xc2x0 C., preferably 0 to 150xc2x0 C. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
The reaction temperature in the reducing reaction is xe2x88x9220 to 150xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 12 hours.
Compound [XXI] is mainly a commercially available amino acid derivative, while compound [XXII] is produced by method N or a commercially available product. (Method H) A compound represented by Formula: 
wherein R1 is an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group, and each of other symbols has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula:
R1xe2x80x2SHxe2x80x83xe2x80x83[XXIII]
wherein R1 has a meaning defined above or a salt thereof with a compound represented by Formula (IX) described above or a salt thereof by a method similar to (Method C) described above or by a method known per se.
Alternatively, a compound represented by Formula (XXIII) or a salt thereof is commercially available or can be produced from a compound represented by Formula:
R1xe2x80x2X1xe2x80x83xe2x80x83[XXIV]
wherein each symbol has a meaning defined above or a salt thereof in accordance with a method known in a literature (for example, methods exemplified in Organic Chemistry of Bivalent Sulfur, Vol.1, p32 (Chem. Publ. Co., New York), Organic Functional Group Preparations, 1 (Academic), etc.).
An xe2x80x9coptionally substituted hydrocarbongroupxe2x80x9d represented by Formula R1 may for example be one exemplified as an xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above. An xe2x80x9cacyl groupxe2x80x9d represented by Formula R1 may for example be one exemplified as an xe2x80x9cacyl groupxe2x80x9d represented by R1 described above.
An xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by Formula R1 may for example be one exemplified as an xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 described above.
(Method I) A compound represented by Formula: 
wherein q2f is 0 to 2n+2 and each of other symbols has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by subjecting a compound represented by Formula: 
wherein L3 is a leaving group and each of other symbols has a meaning defined above or a salt thereof and a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof to a nucleophilic reaction.
A leaving group represented by L3 may for example be one exemplified as a leaving group represented by L1 described above.
This reaction can be performed in accordance with a method similar to (Method G) described above.
Alternatively, a compound represented by Formula (XXV) or a salt thereof can be produced for example by converting a secondary hydroxy group of a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to a leaving group.
In this reaction, a primary hydroxy group of compound [XXVI] or a salt thereof is first protected to form a protected intermediate.
While a protective group employed in this reaction may be any of the protective groups for a hydroxy group employed generally, it is preferably a triphenylmethyl group, a diphenylmethyl group, a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group, etc. having a large steric hindrance, since a secondary hydroxy group exists simultaneously. In the reaction, a halide having a substituent listed above, such as a triphenylmethyl chloride, etc., is condensed with compound [XXVI] or a salt thereof in the presence of a base to form a protected intermediate.
In this reaction, 1 to 5 moles, preferable 1 to 3 moles of a halide and 1 to 10 moles, preferably 1 to 5 moles of a base are employed per 1 mole of compound [XXVI] or a salt thereof.
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
A solvent may for example be an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform Ho and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
While the reaction temperature may vary depending on the substrate employed as well as other conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is 1 to 48 hours, preferably 1 to 24 hours.
An intermediate thus obtained can be subjected to a method similar to that in (Method G) described above to convert a secondary hydroxy group into a leaving group.
An active intermediate thus obtained is deprotected to yield compound [XXV] or a salt thereof.
In this reaction, a deprotection is effected under an acidic condition or as a catalytic hydrogenation. A catalyst employed in a catalytic hydrogenation may for example be a platinum catalyst such as platinum black, platinum oxide and Pt/C, etc., a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, Pd/C, etc. and nickel catalyst such as reduced nickel, oxidized nickel, Raney nickel, Urushibara nickel catalyst, etc.
A solvent is preferably an alcohol such as methanol, ethanol, propanol and isopropanol, etc., an ether such as tetrahydrofuran and dioxane, etc. and an ester such as ethyl acetate, etc.
The reaction temperature is 0xc2x0 C. to 200xc2x0 C., preferably 20xc2x0 C. to 110xc2x0 C. The reaction time is usually 0.5 to 48 hours, preferably 1 to 16 hours. While a reaction is performed usually in an atmospheric pressure, it can be performed under pressure (3 to 10 atm) if necessary.
While the amount of a catalyst employed may vary depending on the type of the catalyst employed, it is usually 0.1 to 20% by weight based on an active intermediate or a salt thereof.
An acid employed in a deprotection under an acidic condition may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
A reaction solvent may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform and dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc.
This reaction employs 1 to 100 moles, preferably 1 to 10 moles of an acid described above per 1 mole of an active intermediate. Some acid can serve also as a solvent.
While the reaction temperature may vary depending on the substrate employed as well as other conditions, it is xe2x88x9220 to 200xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 10 hours.
A compound represented by Formula (XXVI) or a salt thereof can be produced for example by subjecting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt god thereof to a reaction similar to that in Method G or to a method known per se.
A compound represented by Formula (XXVII) or a salt thereof can be produced for example by subjecting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to a deprotection.
While this reaction can be performed various methods, for example, the reductive method similar to catalytic hydrogenation is preferably employed.
A compound represented by Formula (XXVIII) or a salt thereof can be produced for example by subjecting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to a reaction similar to that in Method G or to a method known per se.
As Compound [XXIX], a commercially available amino acid derivative such as serine, etc. is employed mainly. (Method J) A compound represented by Formula: 
wherein each symbol has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof.
This reaction can be performed by a method in (Method A) described above or an analogous method.
As compound [XXX], a commercially available thiodisuccinic acid may for example be employed.
(Method K) A compound represented by Formula: 
wherein each symbol has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein L4 is a leaving group and each of other symbols has a meaning defined above or a salt thereof with a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof.
A leaving group represented by L4 may for example be one exemplified as a leaving group represented by L1 described above.
This reaction can be performed by a method similar to that in (Method G) described above.
Alternatively, a compound represented by Formula (XXXI) or a salt thereof can also be produced for example by reacting a compound represented by Formula: 
or a salt thereof with a compound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof to form an imide followed by a deprotection to form an amino product and a conversion of an amino group to a halogen.
In this reaction, compound [XXXII] or a salt thereof is first condensed with compound [II] or a salt thereof by a method similar to that in (Method E) described above to produce imide. In this process, a cyclization occurs simultaneously.
A deprotection of an imide thus obtained yields an amino product or a salt thereof. This reaction is performed using 1 g of an imide product in 10 volumes of an appropriate organic acid solvent or an inorganic aqueous solution or a mixture. An organic acid is preferably trifluoroacetic acid, etc. An inorganic acid is preferably hydrochloric acid, sulfuric acid, etc.
The reaction temperature is xe2x88x9220 to 100xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C. The reaction time is usually 1 minute to 24 hours, preferably 1 minute to 12 hours.
A resultant amino product or a salt thereof can be substituted by a halogen by a method known in literature, such as methods described in Heterocycles, 24(5), 1331 (1986) and Journal of Organic Chemistry, 58(5), 1159 (1993) to produce compound [XXXI]
In this reaction, 1 to 10 moles, preferably 1 to 3 moles of a diazotizing agent such as sodium nitrite, etc. is reacted per 1 mole of an amino product or a salt thereof in the presence of 1 to 100 moles of a haloacid. A haloacid is preferably hydrochloric acid, hydrobromic acid and hydroiodic acid, etc.
As a reaction solvent, a nitrile such as acetonitrile, etc. and water are preferred.
The reaction temperature is xe2x88x9250 to 100xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 12 hours. Alternatively, a compound represented by Formula (XXXII) or a salt thereof can be produced for example by a compound represented by Formula: 
by a method known in a literature (Tetrahedron Asymmetry, 6(6), 1249 (1995)).
(Method L) A compound represented by Formula: 
wherein each symbol has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example by reacting a compound represented by Formula: 
wherein L5 is a leaving group and each of other symbols has a meaning defined above or a salt thereof with a compound represented by R1SH wherein R1 has a meaning defined above or a salt thereof.
This reaction can be performed by a method described in (Method G) or an analogous method.
A leaving group represented by L5may for example be one exemplified as a leaving group represented by L1 described above.
Alternatively, a compound represented by Formula (XXXV) or a salt can also be produced for example by reacting acompound represented by Formula: 
wherein each symbol has a meaning defined above or a salt thereof with a compound represented by Formula: 
wherein L6 is a leaving group and each of other symbols has a meaning defined above or a salt thereof to convert a hydroxy group into a leaving group.
A leaving group represented by L6 may for example be a halogen atom (for example, chlorine, bromine and iodine, etc.), a substituted sulfonyloxy (for example, methanesulfonyloxy and p-toluenesulfonyloxy, etc.), an acyloxy (such as acetoxy and benzoyloxy, etc.), and an oxy group substituted by a heterocyclic ring or an aryl group (such as succinimide, benzotriazole, quinoline and 4-nitrophenyl, etc.).
Compound [XXXVI] or a salt thereof may be used as a free form, it may be subjected to a reaction as an alkaline metal salt such as lithium, sodium and potassium salts, etc.
In this reaction, 1 to 10 moles, preferably 1 to 5 moles of compound [IIa] or a salt thereof is reacted per 1 mole of compound [XXXVI] or a salt thereof.
Usually, the reaction is performed in a solvent. Such solvent may for example be a halogenated hydrocarbon such as dichloromethane and chloroform, etc., a nitrile such as acetonitrile, etc., an ether such as dimethoxyethane and tetrahydrofuran, etc. as well as dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide, etc.
The addition of a base in this reaction allows the reaction to proceed advantageously. Such base may for example be sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, diisopropylethylamine and pyridine, etc.
While the amount of a base may vary depending on the types of the compound and the solvent employed as well as other reaction conditions, it is usually 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound [XXXVI] or a salt thereof. The reaction temperature is about xe2x88x9250 to 200xc2x0 C., preferably xe2x88x9220 to 150xc2x0 C. While the reaction time varies depending on the type of the compound and the reaction temperature, it is 1 to 72 hours, preferably 1 to 24 hours.
Compound [XXXVI] may be any of commercially available hydroxy-substituted 5-membered and 6-membered amides such as (S)-4-hydroxypyrrolidin-2-one, (R)-4-hydroxypyrrolidin-2-one (DAISO), 3-hydroxypiperidin-2-one (Aldrich), etc., or may be produced by a method known in literatures such as Synthesis, 614 (1978), Tetrahedron Asymmetry, 3(11), 1431 (1992), etc.
Compound [IIa] may be a commercially available product or may be produced by Method N.
(Method M) A compound represented by Formula: 
wherein each symbol has a meaning defined above which is encompassed within compound (I) of the invention or a salt thereof can be produced for example from a compound represented by Formula: 
wherein L is a leaving group and each of other symbols has a meaning defined above or a salt thereof by a method similar to Method G described above.
A leaving group represented by L7 may for example be one exemplified as-a leaving-group represented by L1 described above.
Alternatively, a compound represented by Formula [XXXVIII] or a salt thereof can also be produced for example by subjecting a compound represented by Formula: 
wherein Bz is a benzyl group and each of other symbols has a meaning defined above or a salt thereof to a catalytic hydrogenation by a method known per se (for example a method similar to Method I described above) to obtain a saturated hydroxy form which is then converted into a leaving group.
Compound [XXXIX] or a salt thereof can be produced also in accordance with a method known in a literature (Journal of American Chemical Society, 75, 3413 (1953)). For example, a compound represented by Formula: 
wherein Rb is an optionally substituted hydrocarbon group and Y has a meaning defined above or a salt thereof is subjected to a method similar to Method G described above to form a reduced amino product which is then reacted with a diester derivative of oxalic acid in the presence of a base.
An optionally substituted hydrocarbon group represented by Rb may for example be one exemplified as an optionally substituted hydrocarbon group represented by R1 described above, with a benzyl group being preferred.
In this reaction, a diester of oxalic acid and a base are employed in amounts of 1 to 3 moles, preferably 1 to 2 moles per 1 mole of a reduced amino product.
While various diester derivatives of oxalic acid may be employed, a benzyl derivative capable of being deprotected by a catalytic hydrogenation is preferred.
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
A reaction solvent may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., a halogenated hydrocarbon such as chloroform ahd dichloromethane, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide, etc. as well as water, etc.
While the reaction temperature may vary depending on the substrate employed as well as other conditions, it is 0 to 200xc2x0 C., preferably 0 to 150xc2x0 C. The reaction time is 1 to 24 hours, preferably 1 to 12 hours.
(Method N) A compound represented by Formula: 
or a salt thereof, wherein R has a meaning similar to that of a substituent on ring B in Formula [I] shown above and R30 is an amino group or a halogen which is encompassed within a compound [II] or [IIa] described above or a salt thereof can be produced for example by subjecting a compound represented by Formula: 
wherein R26 has a meaning defined above and W is a cyano group or an aldehyde group or a salt thereof to a reduction or a halogenation which is known per se.
Compound [XXXXII] wherein W is a nitrile was reduced by a known method, such as one using an appropriate reducing agent described for example in xe2x80x9cSHINJIKKENKAGAKUKOZAxe2x80x9d, Vol. 15, Oxidation and Reduction (MARUZEN) to form a benzylamine product [XXXXI]. As a reducing agent, an ordinary nitrile reducing reagent such as a metal hydride including lithium aluminum hydride, etc.
In this reaction 0.5 to 3 moles, preferably 0.5 to 1mole of a reducing agent is employed per 1 mole of Compound [XXXXII].
As a reaction solvent, an ether such as dioxane and tetrahydrofuran, etc. and an aromatic hydrocarbon such as benzene, toluene and xylene, etc. may be employed.
The reaction temperature is xe2x88x9250 to 100xc2x0 C., preferably 0 to 80xc2x0 C. The reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours. A compound [XXXXII] wherein W was an aldehyde was subjected to a known method such as those described in xe2x80x9cJIKKENKAGAKUKOZAxe2x80x9d, Vol. 20, (MARUZEN) and Journal of American Chemical Society, 81, 475 (1959) by converting into an oxime using hydroxylamine followed by a reduction with an appropriate reducing agent to yield a benzylamine product [XXXXI].
An oxime production uses 1 to 3 moles, preferably 1 to 2 moles of hydroxylamine per 1 mole of an aldehyde. This reaction is promoted by an addition of a base. Such base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. The amount employed is 1 to 5 moles, preferably 1 to 3 moles per 1 mole of an aldehyde.
A reaction solvent may for example be an alcohol such as methanol and ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., a nitrile such as acetonitrile, etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide, etc., a sulfoxide such as dimethylsulfoxide, etc. as well as water, etc. The reaction temperature is 0 to 200xc2x0 C., preferably 0 to 150xc2x0 C., and the reaction time is 1 to 48 hours, preferably 1 to 24 hours.
In addition to a catalytic hydrogenation, any ordinary oxime reducing agent such as a metal hydride including lithium aluminum hydride, etc. can be employed as a reducing agent as described in xe2x80x9cSHINJIKKENKAGAKUKOZAxe2x80x9d, Vol.15, Oxidation and Reduction (MARUZEN). The reaction condition is similar to that for reducing a nitrile.
When W is an aldehyde, an appropriate reducing agent was used to form a hydroxy product and then the hydroxy group was halogenated using a halogenating agent to obtain a benzyl halide [XXXXI]. A reducing agent may be an ordinary aldehyde reducing agent described in xe2x80x9cSHINJIKKENKAGAKUKOZAxe2x80x9d, Vol.15; Oxidation and Reduction, with sodium borohydride and lithium aluminum hydride, etc. being employed preferably. The reaction condition is similar to that for a nitrile described above.
A halogenating agent may for example be a halide of an inorganic acid, such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride, etc. and a halogenated hydrogen acid such as hydrochloric acid and hydrobromic acid, etc.
In this reaction, 1 to 3 moles, preferably 1 to 1.5 moles of a halogenating agent is employed per 1 mole of an alcohol.
This reaction is promoted by an addition of a base. Such base may for example be an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc. and a cyclic amine such as pyridine, etc.
A reaction solvent may for example be an ether such as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene and xylene, etc., an ester such as ethyl acetate, etc., and a halogenated hydrocarbon such as chloroform and dichloromethane, etc.
The reaction temperature is xe2x88x9250 to 100xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 10 hours.
Alternatively, compound [XXXXII] may be a commercially available product or may be produced from a compound represented by Formula: 
wherein W has a meaning defined above and X is a halogen atom or a salt thereof and a compound represented by Formula: 
wherein R26 has a meaning defined above or a salt thereof by a method known per se ((Journal of Organic Chemistry, 59(18), 5414 (1994), Bioorganic and Medicinal Chemistry, 6, 15 (1998)) as well as an analogous method.
Compound (I) obtained by any method described above as a free form may be converted in accordance with a standard procedure for example into a salt with an inorganic acid (for example, hydrochloric acid, sulfuric acid and hydrobromic acid, etc.), an organic acid (for example, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fuumaric acid, maleic acid and tartaric acid, etc.), an inorganic base (for example, alkaline metal such as sodium and potassium, etc., alkaline earth metal such as calcium and magnesium, etc., aluminum and ammonium, etc.) or an organic base (for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,Nxe2x80x2-dibenzylethylenediamine, etc.), while compound (I) obtained as a salt may be converted into a free form or other salts according to a standard procedure.
Compound (I) or a salt thereof thus obtained can be purified and recovered using a separation/purification method known per se (for example, condensation, solvent extraction, column chromatography and recrystallization, etc.).
A starting compound for compound (I) according to the invention may be in a form of a salt, including a salt with an inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid, etc.) and a salt with an organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid, etc.). When any of these compound carries an acidic group such as xe2x80x94COOH, etc., a salt with an inorganic base (for example, an alkaline metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, ammonia, etc.) or with an organic base (for example, tri-C1-3 alkylamine such as triethylamine, etc.) may be formed.
In each of the reactions described above, when a starting compound carries as a substituent an amino group, a carboxyl group or a hydroxyl group, then such group is derivatized with a protective group employed ordinarily in a peptide chemistry, which is cleaved after a reaction if desired to yield an intended compound.
A protective group for an amino group may for example be an optionally substituted C1-6 alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl, etc.), phenylcarbonyl, a C1-6 alkyloxycarbonyl (for example, methoxycarbonyl and ethoxycarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl), C7-10 aralkylcarbonyl (for example, benzyloxycarbonyl), trityl, phthaloyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C-1-6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times.
A protective group for a carboxyl group may for example be an optionally substituted C1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, etc.), phenyl, trityl and silyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C16 alkylcarbonyl (for example, formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times.
A protective group for a hydroxyl group may for example be an optionally substituted C1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, etc.), phenyl, a C7-10 aralkyl (for example, benzyl, etc.), a C16 alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl, etc.), C7-10 aralkylcarbonyl (for example, benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C1-6 alkyl, phenyl, a C7-10 aralkyl, nitro, etc., which may occur 1 to about 4 times.
A method for cleaving a protective group is a method known per se or an analogous method, such as a treatment for example with an acid, a base, a reduction, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
Compound (I) or a salt thereof according to the invention has an excellent MMP inhibiting effect, especially an MMP-13 inhibiting effect.
In addition, compound (I) or a salt thereof according to the invention has low toxicity and is safe.
Accordingly, compound (I) or a salt thereof according to the invention having an excellent MMP inhibiting effect, especially an MMP-13 inhibiting effect, is useful as a safe prophylactic and therapeutic agent in a mammal (for example, mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey and human) against osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, periodontosis, corneal ulcer, pathologic bone resorption (such as Behcet""s disease), nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, autoimmune disease (Crohn""s disease and Sjogren""s disease), cancer metastasis, contraception, etc.
A formulation containing compound (I) or a salt thereof according to the invention may be in various dosage forms such as a solid form including powder, granule, tablet, capsule, etc., and a liquid form including syrup, emulsion or solution for injection, etc.
A prophylactic and therapeutic formulation according to the invention can be produced by a customary method such as mixing, kneading, granulation, compaction, coating, sterilization and emulsifying depending on the type of the formulation. The production of a formulation may be in accordance for example with each section in the General Rule of the Formulation under Japanese Pharmacopeia.
While the amount of compound (I) or a salt thereof in a formulation according to the invention may vary depending on the type of the formulation, it is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, more preferably 0.5 to 20% by weight based on the total weight of the formulation.
When compound (I) or a salt thereof is used as a pharmaceutical described above, it may be used as it is or is treated by a standard method if necessary with a pharmaceutically acceptable carrier such as an excipient (for example, starch, lactose, sugar, calcium carbonate and calcium phosphate), a binder (for example, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin and polyvinylpyrrolidone), a lubricant (for example, stearic acid, magnesium stearate, calcium stearate and talc), a disintegrant (for example, calcium carboxymethyl cellulose and talc), a diluent (for example, water for injection and physiological saline) together with appropriate additives (stabilizer, preservative, colorant, flavor, solubilizing agent, emulsifier, buffer, osmotic agent), and administered orally or parenterally in a solid dosage form such as powder, fine powder, granule, tablet, capsule and the like, as well as a liquid form such as an injection formulation. While the dose may vary depending on the types of compound (I) or a pharmaceutically acceptable salt thereof, the administration route, the condition and the age of a patient, a preferred daily dose per kg body weight as compound (I) or a salt thereof is about 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg, which may be divided into 1 to 3 times a day.